A novel histopathological classification of implant periapical lesion: A systematic review and treatment decision tree

Background Implant periapical lesion (IPL), as a peri-implant disease originating from implant apex, maintains coronal osseointegration in the early stage. With the understanding to IPL increasingly deepened, IPL classification based on different elements was proposed although there still lacks an overall classification system. This study, aiming to systematically integrate the available data published in the literature on IPL associated with histopathology, proposed a comprehensive classification framework and treatment decision tree for IPL. Methods and findings English articles on the topic of “implant periapical lesion”, “retrograde peri-implantitis” and “apical peri-implantitis” were searched on PubMed, Embase and Web of Science from 1992 to 2021, and citation retrieval was performed for critical articles. Definite histopathology and radiology of IPL are indispensable criteria for including the article in the literature. The protocol was registered in PROSPERO (CRD42022378001). A total of 509 papers identified, 28 studies were included in this review. In only one retrospective study, 37 of 39 IPL were reported to be at the inflammatory or abscess stage. 27 cases (37 implants) were reported, including acute non-suppurative (1/37, developed to chronic granuloma), chronic granuloma (5/37), acute suppurated (2/37), chronic suppurated-fistulized (6/37), implant periapical cyst (21/37), poor bone healing (2/37), foreign body reaction (1/37). Antibiotics alone did not appear to be effective, and the consequence of surgical debridement required cautious interpretation because of the heterogeneity of lesion course and operation. Implant apicoectomy and marsupialization were predictable approaches in some cases. Conclusions The diversiform nature of IPL in the case reports confirms the need for such histopathological classification, which may enhance the comparison and management of different category.

Introduction Intraoral implants, possessing the advantage of not affecting the integrity of adjacent teeth and the esthetic properties, have frequently been adopted to complete dentition defects since the concept of osseointegration was put forward [1]. Inevitable implant-related complications have also emerged with implant periapical lesion (IPL) first described as an independent disease entity by McAllister et al in 1992 [2]. Compared to the progression and the affected portion of periimplantitis [3], IPL, originating at the implant tip, maintained normal coronal bone in the early stage.
Previous studies briefly classified IPL as active or inactive in accordance with signs and symptoms [4,5]. Understandably, active IPL had a tendency to expand and spread proximally, coronally or facially, with localized pain, mucosal swelling, and fistulas. Different etiologies were proposed to play a part in active IPL such as bone overheating during osteotomy, residual infection of the implant bed, and adjacent endodontic lesion [4,5]. Correspondingly, several terms were used to describe these phenomena, including retrograde periimplantitis, apical periimplantitis and endodontic periimplantitis. Moreover, there also appeared inactive IPL when radiographic manifestations were not relevant to clinical symptoms [4,5]. The overpreparation of implant bed and the placement of the implant around scar tissue were generally considered to be induced causes.
Of concern was the appearance of a cyst at the implant tip. From the case reports [6][7][8], implantation may stimulate epithelial residual or inflammatory transformation to formulate cyst at the implant tip, which might cause localized pain, mucosal swelling, and implant mobility. Radiologically, it was indistinguishable from the previously enumerated IPL types. The previously proposed classifications [4,5,[9][10][11] (Table 1) omitted implant periapical cyst, which is surprising for the symptom that potentially causes implant failure.
At present, there is a lack of a feasible, comprehensive method to both classify and report all conditions present in implant periapical area. At the end, we proposed a novel classification, in which corresponding treatment decision tree was designed to assess its capability to comprise ever-increasing complexity of manifestation and management. Through a systematic review of the literature evidence, the purpose of this study was to use progressively detailed categories as indicators to describe the multiformity of IPL, explicating latent pathogenesis and treatment protocols.

Protocol
This systematic review complied with the PRISMA statement and its protocol was registered in PROSPERO (CRD42022378001).

Focus question
The specific research question was: "What histopathological characteristics are associated with IPL?"

Literature searching
The research was performed in accordance with Cochrane Collaboration recommendations, and it included all published articles related to IPL from 1992 to 2021 on PubMed, Embase and Web of Science. Keywords "retrograde peri-implantitis", "apical peri-implantitis", "implant periapical lesion" were searched in the title/abstract, and citation retrieval was performed for critical articles.

Eligibility criteria
Participants had a history of dental implants. The affected implants needed to be diagnosed as IPL by radiography and histopathology. The results involved radiography, histopathology, and implant outcome. Reviews, conference papers, protocols, non-English publications, and lack of sufficient evidence were excluded.

Studies selection and data extraction
The studies were independently assessed by two reviewers (Wang and Dai) and disagreements were resolved through discussion. Meanwhile, two reviewers independently extracted the information from the literature according to a preset table, which was then further checked by a third reviewer (ZRM). Domains of extraction included author, number of patients, implant site, follow-up, clinical description, histopathology (extracted verbatim), category, interventions, and outcomes.

Quality assessment
All case series reports were assessed via modified The Joanna Briggs Institute (JBI) Critical Assessment Checklist (https://synthesismanual.jbi.global.) and the processes were conducted independently by two reviewers (WJ and DZM). The study was assessed as low risk if it provided more than 75% of the required parameters; And parameters of 50% to 75% were assessed as medium risk; Parameter being less than 50% was classified as high risk.

Information synthesis
The included cases were reviewed for histopathology for the internal integration. Descriptive analysis was used for all extracted information.

Searching results
509 literatures were preliminarily searched, and 28 literatures were finally evaluated after eliminating the reduplicative and substandard literatures. (Fig 1). Table 2 showed the information of IPL extracted after retrieval. There were 27 case reports [6][7][8] and 1 retrospective study [35], all of which were conducted in humans. The following signs and symptoms were frequently mentioned in the case reports: swelling, abscess, localized pain, and fistula. Radiographically, all cases clearly showed radiography in the implant tip, with osseointegration remaining in the implant crown.

Histopathological assessment
Diverse pathogenesis and progression stages of IPL determine the different histopathological manifestations. In a retrospective study [35], histopathology of 37 implants revealed the intrastromal inflammatory cell infiltration, predominantly lymphocytes and plasma cells, of which 26 implants had indications of infection. In case reports, infected granulomatous tissue was associated with generalized chronic and acute cells as well as the presence of neutrophils [13,14,20]. A great number of inflammatory cells, lymphocyte infiltration and necrotic tissue were observed in abscess [16,24]. The squamous epithelium may be explored in cystic lesions, partly infiltrated by dense lymphocytes and macrophages, and partly absent from the intraepithelial lining [8,12,21,23]. A case of foreign body was observed by histopathological examination with well-defined starching granules from rubber gloves [22]. Two IPL cases had undesirable bone healing and both, possessing abnormal bone formation and poor trabecular structure, were aseptic [13,26].

Treatment protocols and results
Variability of the properties did not allow the management of individual patients to be discerned, so the treatment protocols in case reports were rearranged according to the new classification format.
1. Acute non-suppurated (1 case): by the time of intervention, the acute non-suppurative stage had progressed to the chronic granulomatous stage [13].
2. Acute suppurated (2 cases): One case, failing to respond to antibiotics, was covered with collagen membrane after surgical debridement [25]. Tetracycline was disinfected after direct surgical debridement in another case [32]. Both implants ultimately failed to survive.
3. Chronic granuloma (5 cases): Two cases did not respond to antibiotics and were treated with implant apicoectomy and bone graft materials [19,33]. One case performed RCT on the adjacent teeth with the same surgical protocol as the above [13]. In the other two cases, one failed while the other one survived after implant debridement [20,28].
4. Chronic suppurated-fistulized (6 cases): Antibiotic treatment failed in both cases [24,33], followed by the implant failure after surgical debridement in one case and the success with apicoectomy plus GBR in the other. One case was successfully treated with surgical debridement plus GBR and adjacent RCT [14]. The implant was not survived after surgical debridement in two cases [16], but one was reserved by implant apicoectomy [15].
6. Poor bone healing (2 cases): After debridement of the two implants, one implant healed well [13] while the other implant was removed because of the existing lesion [26].

Possibility of bias
Nine papers were assessed as low possibility of bias, 13 as moderate possibility of bias, and 6 as high possibility of bias (Table 3).

Discussion
Replacing the space among the missing teeth with implants is the best alternative to restore the patient's oral morphology and function. However, complex and varied peri-implant diseases generally affect the long-term outcomes of the implant [37]. Early studies mentioned the loss of periapical supporting bone in implants, which was presumed to be related to microbial residue, bone overheating and premature loading [38,39]. At present, IPL is considered to possess the multifactorial induction, with adjacent endodontic lesion having the highest priority [40]. Given the complexity and uncertainty of the pathogenesis, the incomplete recognition of IPL has led to the limitations of previous classification systems. Reiser and Nevins [4] primarily divided IPL into inactive and active forms, which were also employed by Sarmast et al. [9] and Penarrocha-Diago et al [5]. Differently, the former increased the category of implant misplacement and residual infection from etiological consideration. The latter refined the characteristics of inflammatory stage from the stage of lesion progression. Regrettably, the above classifications failed to assess the histopathology of IPL, resulting in the neglection of cyst entities. Sussman et al. [41] believed that the categories "Implant to Tooth" and "Tooth to Implant" explained the potential mutual relationship between adjacent teeth and IPL. This inference was based on radiography, but it was undeniable that IPL sometimes occurred independently from the adjacent teeth. Besides, Was the intervention(s) or treatment procedure(s) clearly described?
Was the postintervention clinical condition clearly described?
Were the adversed events(harms) or unanticipated events identified and described?
Does the case report provide takeaway lessons? Balshi et al. 2007     Kadkhodazadeh and Amid [11] proposed a complex classification of peri-implant disease focusing on the relationship between adjacent teeth and implant, but the interpretation of IPL was limited. Recently, Shah et al. [10] proposed a quantitative classification employing radiology to measure the affected proportion of implant. The failure to consider the pathogenesis of IPL made this classification in the need of combing with other classifications. In this context, the proposed classification provided a comprehensive description of IPL and offered the potential to increase our knowledge and understanding of management. In Table 2, the present possible entity of IPL rather than ordinary inflammatory property was indicated, especially the histopathological evidence of cyst.
For this classification, each category has been subjected to rigorous literature screening and scholars' evaluation while referring to Penarrocha-Diago's proposals [5]. Within the category "implant periapical inflammation", acute non-suppurative phases were less common in the included studies. The localized pain around the implant tip aroused the attention of the implantologists, but the apical radiography could not be observed. Chan et al. [13] reported that the acute suppurative stage progressed to the chronic granuloma stage, which could be detected by apical radiograph a few days after prophylactic antibiotic administration. Apart from radiological differences, the pain response of the former was usually more severe than that of the latter, which showed granulation tissue on biopsy.
The contents of implant periapical abscess described in Penarrocha-Diago's review [5] were confirmed by the histopathology of the included studies. The limited number of cases was due to the exclusion of previous cases focusing on radiology and ignoring histopathology. As a matter of fact, cases at this stage were often described. Pain is particularly intense during this acute suppurative stage. Without early intervention, infection can spread along the implantbone interface, ultimately leading to the implant failure. It can also spread the facial bone-plate and form mucosal fistulas penetrated with oral cavity, allowing oral microbial infiltration. The similarity of Penarrocha-Diago's results provides a degree of assurance with which possible histopathology was integrated.
The term "implant periapical cyst" was first mentioned and reviewed in this classification. Multiple studies reported that implant placement induced cyst formation in implant tip [6,8,30,31]. As described in the case reports, the stimulation of infection or implantation might stimulate epithelial proliferation to form the cyst wall, which was composed of squamous epithelium and could be observed in tissue sections with or without inflammatory cell infiltration, depending on the origin of cyst. In general, patients with implant periapical cysts feel normal in the early stage, but the compression of enlarged cyst can cause various symptoms, such as mucosal swelling, local pain, fistula, and implant mobility. Although cysts (21/35) are the most frequently documented in Table 2, the prevalence is underestimated because some professionals may surgically remove implant periapical tissue without histopathological examination. As it can be difficult to clinically differentiate between implant periapical cyst and other IPL, the definitive diagnosis based on the histopathology study is significant.
Foreign body reaction refers to the inflammatory response caused by the presence of foreign materials at the implant tip that affects bone healing [42]. Foreign bodies, such as glove powder and metal particles from instruments, are usually brought in during the implantation. Nedir et al. [22] examined starch particles in rubber gloves in IPL that caused localized chronic granuloma or delayed hypersensitivity. Radiologically, foreign body reaction did not always present radiolucency, posing a conundrum to distinguish it from initial inflammation.
The incorporation of scar tissue, overpreparation of implant bed, and bone compression for inclusion [40] into the proposed term "poor bone healing" were considered. They are often clinically asymptomatic and radiologically confused with implant periapical cyst, therefore, aseptic, non-cystic histopathological diagnosis is critical. Hence, poor bone healing is not a disease or pathological condition in the new classification. The term is simply defined as "inactive" based on the clinically asymptomatic features and stable lesion ranges seem to require greater caution.
Cases in the literature reported that the treatment of IPL, as an empirical approach rather than the types of IPL (single or multiple), was treated by a particular technique. Treatment decision tree (Fig 3) was attempted to be reported by organizing the same category of information in the IPL. Poor bone healing with radio-only transmission was shown in Fig 2H, which has been suggested by several studies to monitor lesions without medical intervention [43]. Once the radiography increases or the patient experiences pain, surgery is required [43]. In the acute non-suppurative phase shown in Fig 2B, experimental antibiotics seem to be a reasonable conservative option to observe the progression of disease [44], although enrolled cases suggest a great possibility of failure. Reviewing the unincluded literature, it was found that systemic antibiotics for IPL included clindamycin, metronidazole, amoxicillin, cephalexin, penicillin, and cephalosporin [25,26,[45][46][47][48]. Among them, Waasdorp et al [49] and Chang et al [50] respectively used amoxicillin (500mg/d, 10d), amoxicillin (250mg/d, 3d) and acetaminophen(500mg/d, 3d), achieving a surprising success without additional management. At present, there is no consensus on the dose and type of antibiotics for IPL, and its criteria should consider etiology, symptom and open / closed lesions [50].
Symptoms (localized pain and puffiness) and signs (mucosal swelling and fistulas) may occur at various intensifications in different stages of infection. Foreign body reaction is shown in Fig 2G. Implant periapical radiography further confirms the need for surgical intervention [44]. Thorough debridement is identified as the centroid for the prognosis of implant, especially the plaque biofilm on the rough surface of implant [43]. Implant apicoectomy is considered to be prudent because the elevated crown/implant ratio increases the risk of unexpected mechanical complications, although it is currently considered as the most thorough and successful procedure in clinical practice (44/45). Conservative implant surface preparation has been reported, including mechanical curettage [13,25], chemical agents [32], air-abrasive and laser decontamination [51], whereas limited case results suggest that there is no standardized prospective protocol. In this context, a phased debridement protocol was recognized, in which conservative non-resectable surgery was given priority and apicectomy was considered after ineffectiveness [40,43]. Besides, the healing of soft tissue involved in IPL are also of concern, especially in cases of mucosa fistula.
To our knowledge, this is the first comprehensive consideration of implant periapical cyst that reduces the diagnostic complexity of different types of cysts and improves the chances of clinical use. The protocols for removing cyst are not exactly the same as the infection, with the primary privilege concentrating on the treatment of giant implant periapical cyst. While surgical excision was only discussed in the previous study, Troiano et al. [34] provided a potential solution for the successful treatment of a large implant periapical cyst with marsupialization. Biopsy during surgery is considered as a necessary element to identify recurrent cystic or malignant tumors [8,17]. Obviously, this effectively reduces the risk of complications such as implant mobility and fracture caused by direct debridement, thus resulting in large scale of bone defects.
In conclusion, this report, presenting a general classification framework that can highlight the complexity of IPL, is suitable for integrating into the clinical practice. We have done preliminary verification with limited evidence. However, additional cohort studies containing histopathological evidence are necessary to complement and refine the applicability and comprehensiveness of the new classification. This classification is timely for IPL although the ointment is the inability to verify the optimal treatment protocols.